(7) Project Summary / Abstract Physical activity and endurance exercise are stimuli for physiologic adaptation that confer beneficial effects on health including cognition, aging, heart disease, and insulin sensitivity. Skeletal muscle demonstrates significant metabolic plasticity with lipids serving as the preferred fuel source under physiologic stress conditions such as fasting or endurance exercise. From a pathophysiologic perspective, numerous studies have demonstrated that abnormalities in muscle lipid utilization can contribute to the development of obesity, metabolic syndrome, and diabetes. Efficient lipid utilization requires coordinated activity of multiple enzymatic steps including fatty-acid (FA) uptake at the plasma membrane, delivery to the mitochondrial matrix, and FA oxidation (FAO). Major elements of this pathway are under robust transcriptional control as a means to couple gene expression with metabolic need. Recent studies have shown that the nuclear receptor peroxisome proliferator-activated receptor-? (PPAR?) is a critical transcriptional regulator of a broad array of genes necessary for lipid utilization in skeletal muscle. However, the precise molecular basis by which these transcriptional responses are coupled to physiologic stimuli or dysregulated in disease remains poorly understood. As transcriptional control and molecular cooperativity are emerging themes in muscle performance, studies in this proposal investigate a skeletal muscle intrinsic role for a transcription factor termed Kruppel-like factor-15 (KLF15) through a novel molecular module involving PPAR?. Preliminary results central to this proposal identify a tissue-intrinsic role of KLF15 as an essential regulator of skeletal muscle lipid metabolism in response to physiologic (i.e. fasting and exercise) and pathologic (i.e. diet-induced obesity) stress. Specifically, skeletal muscle KLF15 levels are regulated by diverse physiologic and pathologic stimuli that alter lipid utilization. Mice bearing skeletal muscle specific overexpression or deletion of KLF15 demonstrate enhanced and reduced ability for endurance exercise capacity, respectively. Additionally, skeletal muscle restricted KLF15 deficient mice fed a high-fat diet display increased body weight and are glucose intolerant while an anti-parallel effect is observed in skeletal muscle specific KLF15 transgenic mice. Mechanistically, we show that KLF15 binds to, cooperates with, and is requisite for the ability of PPAR? to induce a subset of target genes critical for skeletal muscle lipid utilization. As such, the goals of this proposal are to: (1) To investigate upstream signals governing skeletal muscle KLF15 expression; (2) To elucidate the molecular basis of the KLF15-PPAR? cooperative module in skeletal muscle lipid utilization; (3) To determine the importance of the skeletal muscle KLF15-PPAR? axis in health and disease. The results of these studies may provide the foundation for novel therapies that potentiate the beneficial effects of exercise and combat obesity and diabetes.